! In fibrotic disorders of the lung, including idiopathic pulmonary fibrosis (IPF), lung macrophages have a decisive role in fibrotic repair of injured lung. Macrophages play an integral role in the normal resolution of organ injury but also contribute to the pathogenesis of pulmonary fibrosis by initiating an immune response and by generating reactive oxygen species (ROS), particularly mitochondrial ROS (mtROS). Lung remodeling during pulmonary fibrosis is poorly understood; however, changes in mitochondrial bioenergetics in monocyte- derived macrophages are emerging as a critical determinant of fibrotic repair. The generation of mtROS is linked to calcium (Ca2+) influx into the mitochondria, which is regulated, in part, by the mitochondrial Ca2+ uniporter (MCU). Macrophages in chronic disease typically exhibit apoptosis resistance, and their prolonged survival is associated with disease progression. Metabolic reprogramming to fatty acid oxidation (FAO) is a key feature in macrophage activation. The relative efficiency of FAO is well suited to meet the metabolic requirements necessary for the repair of injured tissue. Our preliminary data show that lung macrophages from IPF subjects have increased expression of peroxisome proliferator-activated receptor coactivator-1 (PGC-1a), a transcription factor that leads to increased enzymatic capacity for FAO, carnitine palmitoyltransferase IA (CPT1A), the rate limiting mitochondrial lipid transporter, and mitochondrial Bcl-2 compared to normal subjects. MCU deficiency attenuates PGC-1a expression, and dominant-negative (DN)-MCU expression abrogates FAO. These findings are relevant because by generating reciprocal bone marrow chimeras using WT and MCU+/- mice, we found mice that received MCU+/- bone marrow were protected from bleomycin-induced pulmonary fibrosis. We hypothesize that MCU mediates pulmonary fibrosis by metabolic reprogramming of lung macrophages to induce apoptosis resistance. We will test this hypothesis with three aims. Aim 1 will test if MCU modulates macrophage metabolic reprogramming to FAO and if MCU is required for pulmonary fibrosis utilizing mice harboring expression of a dominant-negative (DN)-MCU in monocyte-derived macrophages. In Aim 2, we will test if MCU mediates apoptosis resistance by inducing metabolic reprogramming to FAO and enhancing expression of anti-apoptotic Bcl-2 proteins that bind to CPT1a using genetic approaches and in mice harboring expression of DN-MCU or a deletion of Bcl-2 in monocyte-derived macrophages. Aim 3 will provide human biological evidence of the importance of MCU in fibrosis development by determining if modulation of MCU in lung macrophages from IPF subjects regulates FAO and resistance to apoptosis. Understanding the role of MCU in lung macrophages may provide an important target for preventing or halting progression of fibrosis.